February 2018 Edition Vol.12, Issue 2

2018 Forecast Series: Frederick Locke, MD, Vice Chair of the Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center

OBR talked to Frederick Locke, MD, vice chair of the Department of Blood and Marrow Transplant and Cellular Immunotherapy at Moffitt Cancer Center in Tampa, Florida, about the promise and direction of CAR T-cell therapy in blood cancers. Dr. Locke was a co-lead investigator for the ZUMA-1 pivotal trial which led to the FDA approval of Yescarta™, the first approved CAR-T therapy for lymphoma. Dr. Locke also heads the Immune Cell Therapy (ICE-T) initiative at Moffitt, a new clinical and research service delivering the latest immunotherapies to patients.


OBR: Moffitt just treated the first patient commercially in the US with Yescarta, a groundbreaking, newly approved CAR-T for lymphoma. What type of cancer patients are being treated with Yescarta at your institution?

FL: Therapy with Yescarta can be used for patients with certain aggressive B-cell lymphomas who have failed two standard lines of therapy. We are learning how to fit commercial CAR T therapy into our treatment algorithms.  We often see different types of patients who may not fall in line with  clinical trial criteria. There is some leeway to make clinical determinations about who is fit to receive therapy, ie, what prior disease characteristics or comorbidities are there that could theoretically increase risk to patients. Also, there may be some patients who can’t wait to have cells manufactured and the physician may choose to give chemotherapy or other therapy in the interim.  Early referral to a center with CAR T cell experience is critical to allow patients the best chance.


OBR: What training did the practitioners at Moffitt have to undergo, and what are the logistical hurdles to treatment? Will these hurdles become less of an issue in 2018 for Moffitt?

FL: Our center did a lot of ground work during the ZUMA-1 clinical trial to ready ourselves to administer the therapy, including educating staff, nursing, pharmacy, and ICU personnel who would encounter patients. We believe we could treat up to 175 patients per year with commercial CAR T-cell therapy, based on the number of relapsed and refractory acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma patients in Florida. We foresaw the need to hire new faculty, build a larger apheresis unit to handle additional volume, and increase the number of beds in our outpatient treatment facility. We think this therapy is transformational. We are ready and able to administer the therapy.


OBR: There are sites that may list where therapy may be available. Do you have any words of advice?

FL: My advice for the physicians and centers starting out with commercial CAR T therapy: Be cautious. We spent time educating our staff, preparing for expected toxicities and studying treatment algorithms with tocilizumab and corticosteroids to treat toxicities. Also, look at the eligibility criteria from the ZUMA-1 clinical trial of Yescarta and determine which of your patients could safely benefit from the therapy.


OBR: Do you get into the financial side?

FL: I am interested in providing the highest quality cancer care to our patients, however if the therapies are not financially viable we will not be able to sustain the program.  As the CAR T medical liaison to the hospital’s finance group, I have been involved in discussions about the specifics for reimbursement from payers and Medicare for CAR T cell therapy. I do see concerted efforts on all sides; cancer centers, payers, the government and pharmaceutical companies working toward a sustainable model.  I understand it’s an expensive therapy, but we can’t just look at the price tag of the product, we must look at the long term value.  A single infusion of CAR T cells could add many years of life to a leukemia or lymphoma patient.


OBR: Based on what you’re seeing in the clinic and new data at ASH, what critical questions do researchers and providers still have about CAR-Ts? 

FL: The next stage will be other CAR T-cell constructs seeking similar indications. Clinical trials are ongoing in ALL and other diseases, including mantle cell lymphoma, follicular lymphoma and chronic lymphocytic leukemia, to explore CD19 CARs. Combination therapies with checkpoint inhibitors could improve outcomes. We know from ZUMA-1 pre- and post-treatment biopsies, that checkpoint genes are upregulated within the tumor microenvironment.  In addition, we need to better understand the safety profiles of each CD19 CAR T cell therapy, and for each indication. We see differential toxicity rates, with toxicities defined differently using different grading scales. We are also evaluating CAR T cell therapy earlier in the disease course. Can it compete with salvage chemotherapy and autologous transplant? That would be an enormous change in practice if CAR T cell therapy is proven to be the preferred second-line therapy in randomized trials.


OBR: Going into 2018, what do you see ahead in the clinical area in treating blood cancers with CAR-Ts?  What other new cancer therapies and/or combinations of therapies look promising for patients who have blood cancers? 

FL: B-cell maturation antigen (BCMA) CAR T cell therapy induces responses in multiple myeloma. The response rates are fantastic but we don’t yet know if this will be a home run the way CARs were for large-cell lymphoma and acute lymphoblastic leukemia. Could a single infusion lead to years of remission for myeloma? I am not sure and believe we need more data and longer follow-up.  We are optimistic about CD19 CAR T potential in other B-cell malignancies, including mantle cell lymphoma, chronic lymphocytic leukemia, and follicular lymphoma. We are still working on the safest way to administer CAR T to adults with ALL across multiple centers. CD22 is also a potential CAR target for B-cell malignancies.


OBR: What’s your greatest hope for cancer patients today?

FL: I’ve always been interested in immunology and using the immune system to treat cancer. Watching the cellular immunotherapy program grow at our center has been invigorating.  It has truly been an honor to run a multicenter, worldwide clinical trial proving that this new paradigm of treatment, gene therapy altered immune cells, can lead to durable responses in lymphoma patients.  I do see more room for improvements in safety and efficacy outcomes with CARs. I also believe that over the coming years we will see more cellular immunotherapies proven as effective cancer treatments.


OBR: What are your thoughts on the FDA announcement that it plans to approve drugs faster based on very early clinical data if they show a possible survival benefit, in addition to speeding up cancer drug approvals for secondary indications based on single-arm studies?

FL: It is great to have mechanisms for accelerated approval.  ZUMA-1 was approved on the basis of a single-arm, phase II trial. I believe the FDA has been accommodating and engaged with the development of these therapies. We need to continue to make these transformational therapies available so people can benefit from them. We are trying to get rid of cancer for good with CAR T- cell therapy and other cellular immunotherapies and I expect the FDA will continue to work with industry and academia to do so. Ultimately, it benefits patients to get out therapies that work.


OBR: What do you think is the significance of the new data on Yescarta, Kymriah, and/or any other CAR-T therapies that came out of ASH?  

FL:  For aggressive lymphomas the early efficacy results across the therapies appear similar, however a better understanding of the patient populations is needed in order to make direct comparisons. In addition we need longer follow-up for the other CD19 CAR T cell therapies to make comparisons to the ZUMA-1 trial.

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